MICROTUBULES IN TESTICULAR TOXICITY OF CARBENDAZIM

多菌灵睾丸毒性中的微管

基本信息

批准号：
6055938
负责人：
MARION G MILLER
金额：
$ 21.9万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-01 至 2000-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6055938
关键词：
antifungal agents benzimidazoles environmental toxicology intermediate filaments laboratory mouse laboratory rat male microtubules pesticide biological effect pesticide residues testis disorder toxin metabolism vimentin

项目摘要

DESCRIPTION (Adapted from the Investigator's Abstract): Benomyl and its metabolite carbendazim are benzimidazole fungicides which cause testicular toxicity in rats at dose levels where no other organ system is affected. A recent study has supplied strong evidence that carbenazim (CBZ), and not benomyl, is responsible for testicular damage. Histopathologically, testicular toxicity after CBZ administration is characterized by a stage specific sloughing of the seminiferous epithelium. CBZ is known to inhibit microtubule assembly but the relationship of this to the cellular events which underlie sloughing is not known. The hypothesis central to the present proposal is that the singular sensitivity of the testis to CBZ toxicity is the result of disruption of a specific microtubule associated protein (MAP)/tubulin interaction only found in the testis with resultant loss of microtubule assembly and decreased phosphorylation of MAP or tubulin protein(s). A model is presented which addresses the role of testis microtubule vs. intermediate filament structures in the stage specific sloughing induced by CBZ. The first specific aim is to establish that the effect of CBZ on microtubule assembly is specific for testis microtubule assembly and involves disruption of a testis specific MAP-tubulin interaction. The second specific aim is to identify the MAP/tubulin testis-specific proteins which are affected by CBZ and address the possibility that CBZ induced changes in protein phosphorylation play a role in cytoskeletal collapse. The final specific aim will determine the relationship to sloughing of early cytoskeletal changes induced by CBZ administered at dose levels both above and below the sloughing threshold in normal rats and vim-knockout mice. Preliminary immunocytochemical data has indicated that, concomitant with loss of microtubule structure, intermediate filaments collapse towards the basal membrane. A model is proposed which explains the stage specific effects of CBZ in terms of the function of microtubules and intermediate filaments at different stages of germ cell development. The vimentin-knockout mouse provides an excellent experimental model for testing the role of intermediate filaments in the sloughing events which follow CBZ administration.

描述（改编自研究者摘要）：苯菌灵及其代谢物多菌灵是苯并咪唑类杀菌剂，可引起睾丸炎在不影响其他器官系统的剂量水平下对大鼠产生毒性。一个最近的研究提供了强有力的证据表明多菌灵（CBZ），而不是苯菌灵负责睾丸损伤。组织病理学上， CBZ 给药后睾丸毒性的特点是一个阶段生精上皮的特异性脱落。 CBZ 已知可抑制微管组装，但它与细胞事件的关系蜕皮的原因尚不清楚。该假设的核心是目前的建议是，睾丸对 CBZ 具有独特的敏感性毒性是与特定微管相关的破坏的结果蛋白质 (MAP)/微管蛋白相互作用仅在睾丸中发现微管组装损失以及 MAP 或微管蛋白磷酸化降低蛋白质。提出了一个解决睾丸作用的模型特定阶段的微管与中间丝结构 CBZ 引起的蜕皮。第一个具体目标是确定 CBZ 对微管组装的影响对睾丸微管具有特异性组装并涉及睾丸特异性 MAP 微管蛋白的破坏相互作用。第二个具体目标是识别 MAP/微管蛋白睾丸特异性蛋白质，受 CBZ 影响并解决 CBZ 诱导的蛋白质磷酸化变化可能发挥作用在细胞骨架崩溃中。最终的具体目标将决定 CBZ 诱导的早期细胞骨架变化与脱落的关系以高于和低于蜕皮阈值的剂量水平施用正常大鼠和 vim 敲除小鼠。初步免疫细胞化学数据表明，随着微管结构的丧失，中间体细丝向基底膜塌陷。提出了一个模型，其中根据以下功能解释了 CBZ 的阶段特定效果生殖细胞不同阶段的微管和中间丝发展。波形蛋白敲除小鼠提供了一个极好的实验用于测试中间丝在脱落事件中的作用的模型遵循 CBZ 管理。